Summary of Work: The stability of genomes, particularly human, is influenced by opportunities for recombination between long (0.3 - 10 kb) repeats of diverged DNAs such as Alus and LINES, rearrangements between short (4-10 bp) random repeats and replication slippage within micro- and minisatellite DNAs. These repeats are abundant in the genome and represent at-risk motifs (ARMs), because of the high potential for genetic change. Long inverted repeats (IRs) can stimulate recombination and deletion. We found that the level of stimulation in yeast is directly related to the length of IRs and inversely related to the size of spacer between the IRs. A perfect 1 kb IR palindrome increased mitotic recombination approximately 20,000-fold. Large IRs can also stimulate recombination in mammalian cells, leading to novel recombinants. ARMs are especially unstable in the presence of some mutators, indicating that they can be tools for identifying mutators. For example, using pol3-t (DNA-Pol delta) and rad27 (Fen1) mutations that affect DNA replication, we demonstrated that minisatellites can be employed to detect mutators other than those arising from mismatch repair (MMR) defects. ARMs have also enabled us to detect weak mutators, which is important in considering human polymorphic variants that might have a subtle mutator effect or that might exhibit strong synergistic interactions. Using long homonucleotide runs we identified several weak mutators that could exhibit strong pairwise synergistic interactions including: i) dominant negative allele of the MMR gene MSH2; ii) the 5'-<3' exonuclease EXO1, that is potentially involved in MMR and shows strong mutator effects when combined with DNA Pol proofreading defects; iii) a novel mutator allele in pol2 (DNA Pol epsilon) that shows strong mutator effects when combined with an exo1-null. Long homonucleotide runs also proved useful for studying interactions of human MMR genes in yeast. Overexpressed hMSH2 and hMSH6 genes caused a strong mutator phenotype. The high sensitivity also enabled us to detect subtle mutator effects of overexpressed hMSH2 and hMSH3.